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Enrichment of human hematopoietic stem cell activity in the CD34+Thy-
1+Lin- subpopulation from mobilized peripheral blood
L Murray, B Chen, A Galy, S Chen, R Tushinski, N Uchida, R Negrin, G Tricot, S Jagannath and D Vesole
SyStemix Inc., Palo Alto, CA 94304.
The number of CD34+ cells in the peripheral blood of cancer patients is
known to be increased following the administration of high dose
chemotherapy and hematopoietic growth factors. These so-called peripheral
blood stem cell grafts are now frequently used for autologous
transplantation of patients with malignancies. In this report, we address
the question of whether true long-term repopulating pluripotent
hematopoietic stem cells (PHSC) are mobilized into peripheral blood
following chemotherapy plus granulocyte/macrophage colony-stimulating
factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF)
mobilization. We have examined the presence of stem cells in mobilized
peripheral blood (MPB) by using an antibody to the human Thy-1 molecule to
stain the CD34+Lineage- (Lin-) population. The kinetics of mobilization of
CD34+Thy-1+ Lin- cells into peripheral blood were studied, and the
percentage of cells with this phenotype was found to vary widely depending
on the day of leukapheresis. A CD34+Thy- 1+Lin- cell population,
potentially containing PHSCs, was isolated by fluorescence activated cell
sorting (FACS) and analyzed for activity. The multilineage differentiative
capacity of this candidate stem cell- containing population in MPB was
determined using an in vitro long-term culture system, in which cobblestone
area formation was used as a means of detecting PHSCs. We also measured
repopulating capacity by using two in vivo models in which severe combined
immunodeficiency (SCID)-hu mice were implanted with human fetal bone or
thymus grafts. Using these assays, we show that the highest frequency of
cobblestone area-forming cells (CAFC) after 7 weeks of culture was observed
in a subpopulation of CD34+Lin- cells, which expressed low levels of Thy-1.
This cell population was capable of producing both B and myeloid cells, and
maintaining CD34+Lin- cells in these long term cultures. Moreover, the
CD34+Thy-1+Lin- cell subset possessed a higher ability to engraft and to
demonstrate multilineage differentiative potential at 8 weeks in the
SCID-hu bone assay. However, in the SCID-hu thymus model, both Thy-1+ and
Thy-1- subpopulations were capable of donor T-cell engraftment at 6 weeks,
suggesting the presence of cells capable of initiating T lymphopoiesis in
both populations.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 85,
Issue 2,
pp. 368-378,
01/15/1995
Copyright © 1995 by The American Society of Hematology
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